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Antimicrobial Drugs Fahareen-Binta-Mosharraf MNS 1
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Antimicrobial Drugs ChemotherapyThe use of drugs to treat a disease Antimicrobial drugsInterfere with the growth of microbes within a host AntibioticSubstance produced by a microbe that, in small amounts, inhibits another microbe Selective toxicityA drug that kills harmful microbes without damaging the host 2
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3 Principles of Antimicrobial Therapy Administer to an infected person a drug that destroys the infective agent without harming the host’s cells. Antimicrobial drugs are produced naturally or synthetically.
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Basic Terminology An antimicrobial is a chemical substance that has the capacity, in diluted solutions, to kill (biocidal activity) or inhibit the growth (biostatic activity) of microbes The goal of antimicrobial treatment is to render the microbe helpless (either by killing them or inhibiting their replication) and not to hurt the animal being treated Antimicrobials can be classified as: Antibiotics Antifungals Antivirals Antiprotozoals Antiparasitics 5
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Antibiotics Antibiotics work only on bacteria and are described by their spectrum of action (range of bacteria for which the agent is effective) Narrow-spectrum antibiotics work only on either gram-positive or gram-negative bacteria (not both) Broad-spectrum antibiotics work on both gram-positive and gram-negative bacteria (but not necessarily all) Antibiotics can be classified as bactericidal or bacteriostatic Bactericidals kill the bacteria Bacteriostatics inhibit the growth or replication of bacteria 6
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7 Origins of Antibiotic Drugs Antibiotics are common metabolic products of aerobic spore-forming bacteria and fungi. bacteria in genera Streptomyces and Bacillus molds in genera Penicillium and Cephalosporium By inhibiting the other microbes in the same habitat, antibiotic producers have less competition for nutrients and space.
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Table 20.1 8
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Sources Microorganisms: polymyxin are obtained from some Bacillus species Synthesis: Chloramphenicol is now usually produced by a synthetic process Semisynthesis: This means that part of the molecule is produced by a fermentation process using the appropriate microorganism and the product is then further modified by a chemical process. Penicillins and cephalosporins 9
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Table 20.2 10
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How Do Antibiotics Work? Antibiotics work by a variety of mechanisms: Inhibition of cell wall synthesis Damage to the cell membrane Inhibition of protein synthesis Interference with metabolism Impairment of nucleic acids 11
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The Action of Antimicrobial Drugs Figure 20.2 12
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Inhibition of cell wall synthesis 13
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Classes of Antibiotics: β-Lactam antibiotics Beta-lactam antimicrobials - all contain a highly reactive 3 carbon, 1 nitrogen ring Greater than ½ of all antimicrobic drugs are beta- lactams. Mode of action: Primary mode of action is to interfere with cell wall synthesis Penicillins and cephalosporins most prominent beta-lactams 14
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16 Mode of Action Most bacterial cell walls contain peptidoglycan. Penicillins and cephalosporins block synthesis of peptidoglycan, causing the cell wall to lyse. Active on young, growing cells Penicillins do not penetrate the outer membrane and are less effective against Gram-negative bacteria. Broad spectrum penicillins and cephalosporins can cross the cell walls of Gram-negative bacteria.
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Inhibits peptide bridge formation between glycan molecules This causes the cell wall to develop weak points at the growth sites and become fragile 18
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Penicillins Have beta-lactam structure that interferes with bacterial cell wall synthesis Spectrum of activity depends on the type of penicillin
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Natural penicillins: Those produced by fermentation of moulds such as Penicillium notatum and P. chrysogenum Penicillin G and V are narrow-spectrum gram-positive antibiotics Penicillin G is given parenterally Penicillin V is given orally 20
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Semisynthetic penicillins Broader-spectrum penicillins are semi-synthetic Examples include amoxicillin, ampicillin, carbenicillin, ticarcillin, and methicillin 21
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Penicillins Figure 20.6 22
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23 Cephalosporins Account for majority of all antibiotics administered Isolated from Cephalosporium acremonium mold Synthetically altered beta-lactam structure Relatively broad-spectrum, resistant to most penicillinases, & cause fewer allergic reactions Some are given orally; many must be administered parenterally. Generic names have root – cef, ceph, or kef.
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Cephalosporins 2 nd, 3 rd, and 4 th generations more effective against gram- negatives each group more effective against Gram-negatives than the one before with improved dosing schedule and fewer side effects Figure 20.9 24
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25 Cephalosporins 4 generations exist: first generation – cephalothin, cefazolin – most effective against Gram-positive cocci and few Gram-negative second generation – cefaclor, cefonacid – more effective against Gram-negative bacteria third generation – cephalexin, ceftriaxone – broad- spectrum activity against enteric bacteria with beta- lactamases fourth generation – cefepime – widest range; both Gram- negative and Gram-positive
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Polypeptide antibiotics Bacitracin Topical application Against gram-positives Vancomycin Glycopeptide Important "last line" against antibiotic resistant S. aureus Non Beta-lactam Cell Wall Inhibitors 27
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Damage to the cell membrane 29
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30 A cell with a damaged membrane dies from disruption in metabolism or lysis. These drugs have specificity for a particular microbial group, based on differences in types of lipids in their cell membranes. Mode of action Polymyxins interact with phospholipids and cause leakage, particularly in Gram-negative bacteria. Amphotericin B and nystatin form complexes with sterols on fungal membranes which causes leakage.
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Polymyxin B Works by attacking the cell membrane of bacteria (remember that animal cells have cell membranes too) Is a narrow-spectrum, gram-positive antibiotic Not absorbed when taken orally or applied topically Used as an ointment or wet dressing 32
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Alternation of bacterial cell membranes Polymyxins (E) Mainly active against gr-ve “P. aeruginosa” Alteration of fungal cell membranes Amphotericin B “high affinity for ergosterol” (polyene) Nystatin “topically, Candida” Azoles “act by inhibiting ergosterol synthesis” Alternation of cell membrane function 33
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Drugs That Block Protein Synthesis Ribosomes of eukaryotes differ in size and structure from prokaryotes; antimicrobial drugs usually have a selective action against prokaryotes; can also damage the eukaryotic mitochondria 34
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Mode of Action Aminoglycosides: bind to 30S subunit causing it to distort and malfunction; blocks initiation of translation. Eg: Streptomycin, neomycin, gentamycin Tetracyclines: bind to 30S subunit blocking attachment of tRNA Macrolides and Erythromycin: bind 50S subunit and prevents continuation of protein synthesis Chloramphenicol :Binds 50S subunit, inhibits peptide bond formation 35
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The Action of Antimicrobial Drugs Figure 20.4 36
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Streptogramins Binds 50S subunit, inhibits translation Synercid Binds 50S subunit, inhibits translation 37
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Impairment of nucleic acids 38
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39 Mode of Action May block synthesis of nucleotides, inhibit replication, or stop transcription binds and cross-links the double helix drugs that are analogs of purines and pyrimidines insert in nucleic acid, preventing replication.
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Nucleoside and Nucleotide Analogs Figure 20.16a 40
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Nucleoside and Nucleotide Analogs Figure 20.16b, c 41
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Fluoroquinolones Inhibit action of topoisomerase,DNA gyrase Examples include Ciprofloxacin and ofloxacin Urinary tract infections Rifamycins Block prokaryotic RNA polymerase Primarily used to treat tuberculosis and preventing meningitis after exposure to N. meningitidis 42
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Interference with metabolism 44
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Mode of Action Competitive inhibition – drug competes with normal substrate for enzyme’s active site Synergistic effect – an additive effect, achieved by multiple drugs working together, requiring a lower dose of each 45
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Competitive Inhibitors 46
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Sulfonamides (Sulfa drugs) Inhibit folic acid synthesis Most are synthetic Broad spectrum Competitive inhibitor Figure 5.7 47
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Figure 20.13 P-aminobenzoic acid 49
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50 Agents to Treat Fungal Infections Fungal cells are eucaryotic; a drug that is toxic to fungal cells also toxic to human cells Five antifungal drug groups: macrolide polyene mimic lipids, most versatile and effective griseofulvin – stubborn cases of dermatophyte infections, synthetic azoles – broad-spectrum flucytosine – analog of cytosine echinocandins – damage cell walls
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52 Antiparasitic Chemotherapy Antimalarial drugs – quinine, chloroquinine, primaquine, mefloquine Antiprotozoan drugs - sulfonamides, tetracyclines Antihelminthic drugs – mebendazole-broad-spectrum – inhibit function of microtubules, interferes with glucose utilization and disables them
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Antiviral Agents Viruses are intracellular invaders that alter the host cell’s metabolic pathways Selective toxicity is almost impossible due to obligate intracellular parasitic nature of viruses Antiviral drugs act by preventing viral penetration of the host cell or by inhibiting the virus’s production of RNA or DNA 53
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Mode of Action Block penetration into host cell Block transcription or translation of viral genetic material nucleotide analogs acyclovir – a guanine analog AZT – thymine analog - HIV Prevent maturation of viral particles protease inhibitors – HIV 54
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Interferons Human-based glycoprotein produced primarily by leukocytes Cells infected by a virus often produce interferon, which inhibits further spread of the infection Alpha-interferon- drug for treatment of viral hepatitis infections 55
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Synergism occurs when the effect of two drugs together is greater than the effect of either alone. Eg. penicillin and streptomycin in the treatment of bacterial endocarditis. Damage to bacterial cell walls by penicillin makes it easier for streptomycin to enter Indifference occurs when the effect of two drugs together is almost the same as the effect of either alone. Effects of Combinations of Drugs 56
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Antagonism occurs when the effect of two drugs together is less than the effect of either alone For example, the simultaneous use of penicillin and tetracycline is often less effective than when wither drugs is used alone. By stopping the growth of the bacteria, the bacteriostatic drug tetracycline interferes with the action of penicillin, which requires bacterial growth. 57
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Adverse Effects 1. Allergic Reactions: some people develop hypersensitivities to antimicrobials 2. Toxic Effects: some antimicrobials toxic at high concentrations or cause adverse effects 3. Suppression of normal flora: when normal flora killed, other pathogens may be able to grow to high numbers- Superinfection 58
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Resistance to Antimicrobials Some microorganisms inherently resistant to effects of a particular drug Other previously sensitive microorganisms can develop resistance through spontaneous mutations or acquisition of new genes Occurs when bacteria change in some way that reduces or eliminates the effectiveness of the agent used to cure or prevent the infection Can develop through bacterial mutation, bacteria acquiring genes that code for resistance, or other means 60
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Mechanisms of Antibiotic Resistance Enzymatic destruction of drug Some organisms produce enzymes that chemically modify drug Penicillinase breaks β -lactam ring of penicillin antibiotics Alteration of drug's target site Minor structural changes in antibiotic target can prevent binding Changes in ribosomal RNA prevent macrolids from binding to ribosomal subunits 61
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Mechanisms of Antibiotic Resistance Prevention of penetration of drug Alterations in porin proteins decrease permeability of cells Prevents certain drugs from entering Rapid ejection of the drug Some organisms produce efflux pumps Increases overall capacity of organism to eliminate drug o Enables organism to resist higher concentrations of drug o Tetracycline resistance 62
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